Tricyclic Lactams for Use in the Protection of Normal Cells During Chemotherapy

Abstract

This invention is in the area of tricyclic lactam compounds, compositions and methods of protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC) as well as renal cells, from damage associated with DNA damaging chemotherapeutic agents. In one aspect, protection of healthy cells is disclosed using compounds that act as cyclin-dependent kinase 4 / 6 (CDK 4 / 6) inhibitors when administered to subjects undergoing DNA damaging chemotherapeutic regimens for the treatment of proliferative disorders.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of provisional U.S. Application No. 61 / 980,883, filed Apr. 17, 2014, provisional U.S. Application No. 61 / 980,895, filed Apr. 17, 2014, provisional U.S. Application No. 61 / 980,918, filed Apr. 17, 2014, and provisional U.S. Application No. 61 / 980,939, filed Apr. 17, 2014, which are hereby incorporated by reference for all purposes.GOVERNMENT INTEREST[0002]The U.S. Government has rights in this invention by virtue of support under Grant No. 5R44AI084284 awarded by the National Institute of Allergy and Infectious Diseases.FIELD OF THE INVENTION[0003]This invention is in the area of tricyclic lactam compounds, compositions, and methods of protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC) as well as renal cells, from damage associated with DNA damaging chemotherapeutic agents.BACKGROUND[0004]Chemotherapy refers to the use of cytotoxic (typically DNA damaging) drugs to treat a range of pr...

AI Technical Summary

Benefits of technology

The patent describes a method to protect healthy cells in the body, such as hematopoietic stem cells and kidney cells, from the toxic effects of chemotherapy. This is achieved by using a special compound called a tricyclic lactam that selectively targets certain proteins involved in cell replication. The use of this compound allows for a higher dose of chemotherapy to be used while minimizing the toxic effects on healthy cells. The tricyclic lactam compound can also provide temporary pharmacologic quiescence of healthy cells, reducing the risk of anemia, lymphopenia, thrombocytopenia, and neutropenia.

Problems solved by technology

Chemotherapeutic compounds tend to be non-specific and, particularly at high doses, toxic to normal, rapidly dividing cells.

This often leads to a variety of side effects in patients undergoing chemotherapy.

Myelosuppression continues to represent the major dose-limiting toxicity of cancer chemotherapy, resulting in considerable morbidity along with the potential need to require a reduction in chemotherapy dose intensity, which may compromise disease control and survival.

In addition to bone marrow suppression, chemotherapeutic agents can adversely affect other healthy cells such as renal epithelial cells, resulting potentially in the development of acute kidney injury due to the death of the tubular epithelia.

Acute kidney injury can lead to chronic kidney disease, multi-organ failure, sepsis, and death.

Dose reductions or cycle delays, however, diminish the effectiveness and ultimately compromise long-term disease control and survival.

Unfortunately, there is concern that many chemoprotectants, such as dexrazoxane and amifostine, can decrease the efficacy of chemotherapy given concomitantly.

However, these recombinant proteins are expensive.

Moreover, EPO has significant toxicity in cancer patients, leading to increased thrombosis, relapse and death in several large randomized trials.

Consequently, their use is restricted and not readily available to all patients in need.

Further, while growth factors can hasten recovery of some blood cell lineages, no therapy exists to treat suppression of platelets, macrophages, T-cells or B-cells.

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